An Investigation Into The Prevention Of Cisplatin-Induced Nephrotoxicity By Dichloroacetate
Date
2016
Authors
Galgamuwa Arachchige, Ramindhu
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Abstract
Cisplatin is a highly effective anticancer drug used to treat a
range of cancers. However, cisplatin use often leads to
nephrotoxicity, which limits its clinical effectiveness.
Dichloroacetate (DCA), which has been used to treat lactic
acidosis, has emerged over the past decade as a novel anticancer
medication. This is primarily due to its ability to reverse the
glycolytic phenotype of cancer cells (the Warburg effect). A
number of clinical trials assessing its anticancer properties are
in progress. It is therefore highly likely that DCA will be used
in combination with other well-established anti-cancer drugs.
Hence, in this study the effects of DCA on the antineoplastic and
nephrotoxic effects of cisplatin were studied in a mouse model of
cisplatin-induced acute kidney injury (AKI).
It was demonstrated that DCA did not attenuate the antineoplastic
activity of cisplatin while it significantly attenuated the
cisplatin-induced nephrotoxicity; as detected by an attenuation
of cisplatin-induced increase in serum markers of kidney injury
(serum creatinine and blood urea nitrogen), renal tubular
apoptosis, renal oxidative stress and cisplatin-induced changes
in kidney histology, leading to increased survival of mice.
Additionally, pretreatment with DCA accelerated renal tubular
epithelial cell (RTEC) regeneration after cisplatin-induced renal
damage. However, we also found that DCA co-treatment with
cisplatin surprisingly increased the urinary markers of tubular
injury. This response to DCA was attributed to faster RTEC
regeneration and dead cell debris clearance from the renal
tubular lumen.
Further examination of the mechanism by which DCA attenuates
cisplatin nephrotoxicity revealed that DCA did not reduce kidney
platinum accumulation, reduce the formation of a highly reactive
thiol toxin in the kidney or reduce serum TNF-α levels.
Whole kidney transcriptome sequencing revealed a key
nephroprotective mechanism; DCA co-treatment prevented
mitochondrial dysfunction and preserved the energy-generating
capacity of the kidneys by preventing the cisplatin-induced
downregulation of genes involved in fatty acid and glucose
oxidation, and of genes involved in the Krebs cycle and oxidative
phosphorylation.
Thus the mechanism by which DCA ameliorates nephrotoxicity
appears to be two fold. Firstly DCA prevents cisplatin-induced
mitochondrial dysfunction and thereby renal ATP depletion, renal
oxidative stress and RTEC apoptosis. Secondly, as a result of the
maintenance of ATP levels and the absence of oxidative stress
there is an increased capacity for RTEC regeneration.
The findings of this study raise the possibility of combining DCA
with cisplatin therapy to reduce nephrotoxicity. This could allow
escalation of cisplatin doses for greater therapeutic
effectiveness in cancer chemotherapy. Furthermore, work presented
in this thesis opens a new research direction exploring DCA as
potentially the first medication for the treatment of drug
induced AKI, which may increase the therapeutic usage of
nephrotoxic medications and reduce the mortality and morbidity
associated with toxic AKI.
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Cisplatin-Induced Nephrotoxicity, Dichloroacetate
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